Infertility affects one in six couples, with, in one out of two cases, a deficiency of the male partner.
Male infertility presents highly variable phenotypes. One of the most common is asthenozoospermia, characterized by the decrease or absence of sperm motility [see Publicover S J, Barratt C L. Sperm motility: things are moving in the lab! Mol Hum Reprod. 2011 August; 17(8):453-6.]
Assisted reproduction technology (ART) is the term used to describe the methods used to aid couples and includes, depending on the severity of the male infertility: intrauterine insemination (IUI) for mild, in vitro fertilization (IVF) for moderate, and intra-cytoplasmic sperm injection (ICSI) for men with severe sperm dysfunction.
In some cases of azoospermia or oligozoospermia, the recovery of sperm directly from the testicle or epididymis is required.
Freezing of sperm samples is often necessary in ART. However, a major disadvantage of freezing samples is that spermatazoa that have been previously frozen, once thawed, have a reduced motility compared to fresh sperm samples, with lower amount of progressive sperm.
Moreover, in farm animals, for which artificial insemination AI is heavily used, the decreased motility of frozen sperm means that sperm concentration in straws must be increased and this reduces the overall success of the method.
The use of non-toxic agents that can increase sperm motility thus presents a strong therapeutic value in the context of medically assisted reproduction.
As spermatazoa mature in a heterogeneous manner, individual testicular spermatazoa that have been collected from a patient presenting with azoospermia or oligozoospermia are often chosen for use in medically assisted reproduction, based on their response to molecules that activate sperm motility. Very few or none, depending of the country, of these molecules are available for clinical use today, thus leaving clinicians without tools to make this selection.
As well as for in vitro fertilisation (IVF) techniques, these agents are also of interest for artificial insemination (AI), for example, where sperm is injected into the vaginal tract or uterus (IUI) of the female, because they increase the motility of the spermatozoa in the female genital tract, and therefore increase the chance of fertilization occurring.
Thus, such agents also impact the success rate of in vitro fertilization techniques, not only for therapeutic use in humans, but also for industrial reproduction use in numerous species, like horses, pigs, cattle, and birds, like for example, turkeys.
In the past, non-selective phosphodiesterase inhibitors like pentoxifylline (PTF) were used to increase the sperm motility in humans. However, while these molecules do show increased acceleration in mobile spermatazoa, a significant disadvantage has been premature stimulation of the acrosome reaction (AR). This leads to the sperm's inability to penetrate the oocyte once it reaches it.
Recently other PDE inhibitors have been examined in a small clinical trial [Tardif S, Madamidola O A, Brown S G, Frame L, Lefièvre L, Wyatt P G, Barratt C L, Martins Da Silva S J. Clinically relevant enhancement of human sperm motility using compounds with reported phosphodiesterase inhibitor activity. Hum Reprod. 2014, Oct. 10; 29(10)2123-35.] Of 43 commercially available molecules with PDE inhibitory activity, six showed a strong effect on poor motility in Phase I, and in Phase II three of these compounds were identified as “promising candidates for further study”.
Another PDE inhibitor, papaverine, has also been considered as an alternative to pentoxifylline (see for example Terriou et al. 2015, Gynécologie Obstétrique et Fertilité 43, p. 786-790).
Therefore, there still exists a strong need for non-toxic agents that increase the motility of sperm cells to be used in ART procedures including, for example, AI, IUI, IVF, including intra-cytoplasmic sperm injection (ICSI) for therapeutic use in humans. There is a need for non-toxic agents that activate the motility of spermatazoa.
There is a need for agents that allow the selection of individual spermatozoa for use in ART including IVF, including intra-cytoplasmic sperm injection (ICSI).
There is also a strong need for agents that may be used to increase male fertility in industrial artificial insemination procedures in animals. In particular, there is a need for molecules that can increase the number of progressive sperm from a frozen straw (sample).
There is a need for an agent that can increase the fertilisation capability of a sperm population contained in a sample for use in industrial artificial insemination procedures in animals.
There is a need for an agent that is capable of activating/increasing the motility of fresh spermatozoa as well as of those that have been previously frozen.
There is a need for an agent that can activate the motility of testicular, epididymal and/or ejaculated sperm in bovine, porcine, ovine, birds, such as for example chicken and turkeys, equine, goat, and domestic animals, in particular cats and dogs.
There is a need for agents that can activate the motility of testicular, epididymal and/or ejaculated sperm in humans.